JP2023532787A - Crystalline forms of upadacitinib, processes for its preparation and uses thereof - Google Patents

Abstract

The present invention relates to a novel crystalline form of upadacitinib and a process for its preparation. The present invention also provides pharmaceutical compositions containing upadacitinib crystalline forms, uses of upadacitinib crystalline forms for preparing JAK1 inhibitor medicaments, and rheumatoid arthritis, Crohn's disease, ulcerative colitis, atopic dermatitis and psoriatic arthritis. of a crystalline form of upadacitinib for the preparation of a medicament for treating The crystalline forms of upadacitinib provided by the present invention have one or more improved properties compared to the prior art and have significant value for future drug optimization and development. [Formula 1] JPEG2023532787000023.jpg72164 [Selection] Fig. 1

Description

(Technical field)
The present invention relates to the field of chemical crystallography, and in particular to novel crystalline forms of upadacitinib, methods of preparation and uses thereof.

Rheumatoid arthritis is an autoimmune disease that can cause chronic inflammation in joints and other parts of the body, resulting in permanent joint damage and deformities. If untreated, rheumatoid arthritis can lead to substantial disability and pain due to impaired joint function, ultimately resulting in shorter life expectancy. Crohn's disease is an inflammatory bowel disease. Symptoms usually include abdominal pain, diarrhea, fever, and weight loss. Patients with this disease are at high risk for colon cancer. Ulcerative colitis is a chronic disease that causes inflammation and ulceration of the colon and rectum. The main symptoms are diarrhea with abdominal pain and bloody stools. Symptoms usually progress slowly and vary in severity. Common symptoms of atopic dermatitis include itching, redness, and cracking of the skin. Patients with atopic dermatitis may also have hay fever and asthma. Psoriatic arthritis is an inflammatory arthritis associated with psoriasis, accompanied by psoriatic eruptions and pain, swelling, tenderness and stiffness in the joints and surrounding soft tissues, and dyskinesias.

Janus kinase 1 (JAK1) is a target of immune-inflammatory diseases, and inhibitors thereof are beneficial in the treatment of immune-inflammatory diseases such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, atopic dermatitis, and psoriatic arthritis. is.

Upadacitinib is a second-generation oral JAK1 inhibitor developed by AbbVie with high inhibitory selectivity for JAK1. The chemical name for upadacitinib is (3S,4R)-3-ethyl-4-(3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2 ,2-trifluoroethyl)pyrrolidine-l-carboxamide, and has the following structure:

A crystalline form is a solid material whose constituents are arranged in a highly ordered microstructure, forming a crystal lattice that extends in all directions. Compounds may exist in one or more salts, crystalline forms, or co-crystals, the existence and properties of which cannot be predicted with certainty. Different crystalline forms of the drug substance have different physicochemical properties, which can affect the in vivo dissolution and absorption of the drug, and to some extent further affect the clinical efficacy and safety of the drug. Especially for some poorly soluble oral solid or semi-solid dosage forms, the crystalline form can be important to the performance of the formulation. Additionally, the physical properties of the crystalline form can be important to the manufacturing process. For example, certain polymorphs may be prone to solvate formation or have poor impurity removal capabilities. Polymorphisms are therefore an important part of drug research and drug quality control.

Amorphous forms are non-crystalline materials that do not have long-range order. Typically, the amorphous form exhibits a broad "halo" XRPD pattern. Molecules in an amorphous solid are randomly arranged. Due to the low thermodynamic stability of amorphous drug substances, they tend to undergo crystalline transformations during the manufacturing process and storage. Poorly stable amorphous drug substances may lead to changes in drug bioavailability, dissolution rate, etc., which in turn may lead to changes in the clinical efficacy of the drug.

According to the FDA Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry, a pharmaceutical co-crystal is two or more different molecules (one of which is are APIs). One advantage of pharmaceutical co-crystals is to enhance the bioavailability and stability of the formulation. Another advantage of co-crystals is that they produce better solid forms for APIs that lack ionizable functional groups, a prerequisite for salt formation. Both succinic acid and adipic acid are listed in the Generally Recognized As Safe (GRAS) and FDA Inactive Ingredients databases, demonstrating that succinic acid and adipic acid are safe pharmaceutical co-crystal formers. showing.

WO2017066775A1 discloses upadacitinib free form A, form B, form C, form D, amorphous and salts thereof. This patent application discloses that Forms A and B have poor crystallinity and stability and can be easily dehydrated to become amorphous. Form D can only be obtained with low water activity. In addition, the crystallization process of Form D is slow and difficult to repeat. Form D converts to form C at high water activity. Form C has better properties compared to other forms of upadacitinib free form disclosed in WO2017066775A1. However, it has the disadvantage of poor reproducibility and is difficult to crystallize from solution.

WO2020063939A1 discloses the acetic acid solvate of upadacitinib (form CSI). WO2020115213A1 discloses an acetic _{acid solvate of Form A HOAC /} B _HOAC with Form A HOAC being the same as Form CSI. The inventors of the present invention have found that the acetic acid solvate has poor stability and does not meet the requirements for pharmaceutical development.

To overcome the shortcomings of the prior art, there is still a need for crystalline forms that meet pharmaceutical requirements for the development of drugs containing upadacitinib. The inventors of the present invention have surprisingly discovered crystalline forms CSVI and crystalline forms CSVII of upadacitinib, which are characterized by solubility, hygroscopicity, purification ability, stability, adhesiveness, compressibility, flowability, It has advantages in at least one aspect, such as in vitro and in vivo solubility, and bioavailability. In particular, crystalline form CSVI and crystalline form CSVII have good solubility, good stability, high solubility, and safe co-crystal formers, which solve the problems existing in the prior art, is of great importance in the development of drugs containing

The present invention is to provide a novel crystalline form of upadacitinib, its preparation method, pharmaceutical composition and use.

According to the objects of the present invention, there is provided a succinic acid co-crystal Form CSVI of upadacitinib (hereinafter referred to as Form CSVI).

According to one aspect of the invention, the X-ray powder diffraction pattern of Form CSVI is 4.7°±0.2°, 6.2°±0.2° and 22.7° using CuKα radiation. One or two or three characteristic peaks are shown at 2-theta values of ±0.2°. Preferably, the X-ray powder diffraction pattern of Form CSVI is 4.7° ± 0.2°, 6.2° ± 0.2° and 22.7° ± 0.2° two-theta using CuKα radiation. values show a characteristic peak.

Furthermore, the X-ray powder diffraction pattern of form CSVI shows 2-theta values of 15.8°±0.2°, 17.3°±0.2° and 23.5°±0.2° using CuKα radiation. shows one, two or three characteristic peaks. Preferably, the X-ray powder diffraction pattern of Form CSVI is 15.8° ± 0.2°, 17.3° ± 0.2° and 23.5° ± 0.2° two-theta using CuKα radiation. values show a characteristic peak.

In addition, the X-ray powder diffraction pattern of form CSVI shows 2-theta angles of 11.1°±0.2°, 14.1°±0.2° and 13.1°±0.2° using CuKα radiation. The values show one, two or three characteristic peaks. Preferably, the X-ray powder diffraction pattern of Form CSVI has 2-theta values of 11.1°±0.2°, 14.1°±0.2° and 13.1°±0.2° using CuKα radiation. shows a characteristic peak at .

According to another aspect of the invention, the X-ray powder diffraction pattern of Form CSVI has 2-theta values of 4.7°±0.2°, 6.2°±0.2°, 22.7°±0. 2°, 15.8°±0.2°, 17.3°±0.2°, 23.5°±0.2°, 11.1°±0.2°, 14.1°±0. X-ray using CuKα radiation at 2°, 13.1°±0.2°, 20.2°±0.2°, 16.2°±0.2°, 21.3°±0.2° A powder diffraction pattern is shown. Preferably, the X-ray powder diffraction pattern of Form CSVI is 4.7°±0.2°, 6.2°±0.2°, 22.7°±0.2°, 15° using CuKα radiation. It exhibits characteristic peaks at 2θ values of 0.8°±0.2° and 14.1°±0.2°.

Without suggesting any limitation, the X-ray powder diffraction pattern of Form CSVI is substantially as shown in FIG.

Without limitation, the thermogravimetric analysis (TGA) curve for Form CSVI is substantially as shown in Figure 2, which shows a weight loss of 1.2% when heated to 100°C. indicate.

By way of non-limiting example, the differential scanning calorimetry (DSC) curve of Form CSVI is substantially as shown in Figure 3, which exhibits an endothermic peak when heated to about 124°C.

Without limitation, the molar ratio of succinic acid to upadacitinib in Form CSVI is from 0.4:1 to 1.1:1, preferably from 0.5:1 to 1:1.

According to the object of the present invention, there is also provided a process for preparing Form CSVI. This method
1) adding upadacitinib and succinic acid to a mixture of esters and ethers and stirring to obtain Form CSVI, or 2) adding upadacitinib and succinic acid to a mixture of ethers, alcohols, water and alkanes or a mixture of alcohols and alkanes. and stirring to obtain Form CSVI.

Furthermore, said ester is preferably isopropyl acetate, said ether is methyl tert-butyl ether, said alcohol is n-propanol, isopropanol, isobutanol or n-butanol, said alkane is n-heptane is.

Furthermore, in method 1), upadacitinib and adipic acid were added at a molar ratio of 1:1 to 1:3. The ester/ether volume ratio is between 1:1 and 1:3. The stirring temperature is preferably 0°C to 50°C. The duration of said stirring preferably exceeds 12 hours.

Furthermore, in method 2), upadacitinib and adipic acid were added at a molar ratio of 1:0.6 to 1:2.

Form CSVI of the present invention has the following advantages:
(1) Compared to the prior art, form CSVI has higher solubility. In particular, in FaSSIF, FeSSIF and pH=7.4 PBS, the solubility of form CSVI is 4-8 times higher than that of prior art form C.

Higher solubility is beneficial for improving the in vivo absorption and bioavailability of the drug and thus improving the efficacy of the drug. In addition, due to the higher solubility, the drug dose can be reduced without affecting efficacy, thereby reducing drug side effects and improving drug safety.

(2) Form CSVI drug substance of the present invention has good stability. The crystalline state of Form CSVI drug substance does not change for at least 6 months when stored under conditions of 40° C./75% RH (relative humidity). The crystalline state of CSVI drug substance does not change for at least one month when stored under conditions of 60°C/75% RH (sealed). Chemical purity exceeds 99.8% and remains virtually unchanged during storage. After mixing Form CSVI with excipients to form a formulation and storing under conditions of 25° C./60% RH and 40° C./75% RH, the crystalline state of Form CSVI formulation does not change for at least 3 months. The chemical purity of the drug substance in formulation exceeds 99.8% and remains substantially unchanged during storage.

Good stability of drug substances and products under accelerated and stress conditions is very important for drug development. During storage, transportation, and manufacturing, drug substances experience hot and humid conditions due to seasonal, regional climate, and weather variations. Form CSVI drug substance and drug product have good stability under these stress conditions, which is beneficial to avoid affecting drug quality due to crystal transformation or reducing purity during drug storage.

Good physical and chemical stability of the drug substance ensures that no crystal transitions occur and no impurities are formed during manufacture and storage. Form CSVI has good physical and chemical stability, ensures consistent and controllable quality of drug substance and drug product, and eliminates toxicity and Minimize side effects.

(3) Compared with the prior art, Form CSVI formulation has better in vitro dissolution. The dissolution of form CSVI formulation in 0.1N HCl in 30 minutes is up to 85%, meeting the criteria for rapid dissolution. In 0.1 N HCl, the dissolution rate of Form CSVI (CSVI Agent) formulation is higher than that of Form C formulation. It is speculated that Form CSVI has an in vivo bioavailability advantage over Form C formulations.

Drug dissolution is a prerequisite for drug absorption. Different crystalline forms of the drug may cause different in vivo dissolution kinetics, ultimately resulting in different clinical efficacy. According to the "BCS (Biopharmaceutics Classification System) Guidelines", an in vitro dissolution test is a useful tool for predicting the in vivo performance of a product. Good in vitro dissolution of the Form CSVI drug product provided by the present invention can lead to higher in vivo absorption, better in vivo exposure, thereby improving drug bioavailability and efficacy. A higher intrinsic dissolution rate of Form CSVI drug substance is beneficial for the drug to achieve peak concentrations in plasma sooner after administration, thus ensuring rapid drug action.

According to the objects of the present invention, there is provided adipic acid co-crystal Form CSVII of upadacitinib (hereinafter referred to as Form CSVII).

According to one aspect of the present invention, the X-ray powder diffraction pattern of Form CSVII is 4.8°±0.2°, 6.0°±0.2° and 22.4° using CuKα radiation. One or two or three characteristic peaks are shown at 2-theta values of ±0.2°. Preferably, the X-ray powder diffraction pattern of Form CSVII is 4.8° ± 0.2°, 6.0° ± 0.2° and 22.4° ± 0.2° two-theta using CuKα radiation. values show a characteristic peak.

Furthermore, the X-ray powder diffraction pattern of Form CSVII shows 2-theta values of 21.1°±0.2°, 15.4°±0.2° and 16.2°±0.2° using CuKα radiation. shows one, two or three characteristic peaks. Preferably, the X-ray powder diffraction pattern of Form CSVII is 2θ of 21.1° ± 0.2°, 15.4° ± 0.2° and 16.2° ± 0.2° using CuKα radiation. values show a characteristic peak.

In addition, the X-ray powder diffraction pattern of Form CSVII shows 2-theta values of 25.4°±0.2°, 12.8°±0.2° and 20.2°±0.2° using CuKα radiation. shows one, two or three characteristic peaks. Preferably, the X-ray powder diffraction pattern of CSVII has 2-theta values of 25.4°±0.2°, 12.8°±0.2° and 20.2°±0.2° using CuKα radiation. shows a characteristic peak at .

According to another aspect of the invention, the X-ray powder diffraction pattern of Form CSVII is 4.8°±0.2°, 6.0°±0.2°, 22.4° using CuKα radiation. ±0.2°, 21.1°±0.2°, 15.4°±0.2°, 16.2°±0.2°, 25.4°±0.2°, 12.8° 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 characteristic peaks are shown.

Without implying any limitation, the X-ray powder diffraction pattern of Form CSVII is substantially as shown in FIG.

Without limitation, the TGA curve of Form CSVII is substantially as shown in Figure 8, showing a weight loss of 0.1% when heated to 100°C.

Without implied any limitation, the DSC curve of Form CSVII is substantially as shown in Figure 9, which exhibits an endothermic peak when heated to about 105°C.

Without limitation, the molar ratio of adipic acid to upadacitinib in Form CSVII is from 0.4:1 to 1.1:1, preferably from 0.5:1 to 1:1.

According to the object of the present invention there is also provided a process for preparing Form CSVII. The method comprises the steps of: 1) adding upadacitinib and adipic acid to a mixture of esters and ethers and stirring to obtain Form CSVII; or 2) adding upadacitinib and adipic acid to a mixture of alcohols and alkanes, stirring and simply releasing and then drying to obtain Form CSVII.

Further, said ester is isopropyl acetate, said ether is methyl tert-butyl ether, said alcohol is n-propanol, isopropanol, n-butanol or isobutanol, and said alkane is n-heptane. .

Furthermore, in method 1), upadacitinib and adipic acid were added at a molar ratio of 1:1 to 1:3. The ester/ether volume ratio is between 1:1 and 1:10. The stirring temperature is preferably 0°C to 50°C. The duration of said stirring preferably exceeds 12 hours.

Furthermore, in method 2), upadacitinib and adipic acid were added at a molar ratio of 1:0.6 to 1:2. The temperature of the vacuum drying is preferably 40°C to 80°C.

Form CSVII of the present invention has the following advantages:
(1) Compared to the prior art, Form CSVII has higher solubility. Specifically, in FaSSIF, FeSSIF and pH=7.4 PBS, the solubility of Form CSVII is 4-8 times higher than that of prior art Form C.

Higher solubility is beneficial for improving the in vivo absorption and bioavailability of the drug and thus improving the efficacy of the drug. In addition, due to the higher solubility, the drug dose can be reduced without affecting efficacy, thereby reducing drug side effects and improving drug safety.

(2) Form CSVII drug substance of the present invention has good stability. The crystalline state of Form CSVII drug substance does not change for at least 6 months when stored under conditions of 25° C./60% RH. The crystalline state of Form CSVII drug substance does not change for at least 6 months when stored under conditions of 40° C./75% RH (sealed). Form CSVII drug substance is unchanged for at least one month when stored under conditions of 60°C/75% RH (sealed). The chemical purity exceeds 99.9% and remains virtually unchanged during storage. After mixing Form CSVII with excipients to form a formulation and storing under conditions of 25° C./60% RH and 40° C./75% RH, the crystalline state of Form CSVII formulation does not change for at least 3 months. The chemical purity of the drug substance in the formulation remains substantially unchanged during storage.

Good stability of drug substances and products under accelerated and stress conditions is very important for drug development. During storage, transportation and manufacturing, drug substances are exposed to hot and humid conditions due to seasonal, local climate and weather. Form CSVII has good stability under these stress conditions, which is beneficial to avoid affecting drug quality due to crystal transformation or reducing purity during drug storage.

Good physical and chemical stability of the drug substance ensures that no crystal transitions occur and no impurities are formed during manufacture and storage. Form CSVII has good physical and chemical stability, ensures consistent and controllable quality of drug substance and drug product, and reduces toxicity and Minimize side effects.

(3) Compared to the prior art, Form CSVII has better in vitro dissolution. In 0.1N HCl, dissolution of Form CSVII formulation is up to 85% in 30 minutes, meeting the criteria for rapid dissolution. In 0.1N HCl and pH 6.8 PBS, the dissolution rate of Form CSVII formulation is higher than that of Form C formulation. It is speculated that Form CSVII has in vivo bioavailability advantages compared to Form C formulations.

Drug dissolution is a prerequisite for drug absorption. Different crystalline forms of drug may result in different in vivo dissolution kinetics and ultimately different clinical efficacy. According to the "BCS (Biopharmaceutics Classification System) Guidelines", an in vitro dissolution test is a useful tool for predicting the in vivo performance of a product. Good in vitro dissolution of Form CSVII drug product provided by the present invention can lead to higher in vivo absorption and better in vivo exposure, thereby improving drug bioavailability and efficacy. A higher intrinsic dissolution rate of Form CSVII drug substance is beneficial for the drug to achieve peak concentrations in plasma sooner after administration, thus ensuring rapid drug action.

According to an object of the present invention, a pharmaceutical composition is provided, said pharmaceutical composition comprising a therapeutically effective amount of Form CSVI or Form CSVII and a pharmaceutically acceptable excipient.

Furthermore, the present invention provides use of Form CSVI or Form CSVII for preparing a JAK1 inhibitor.

Further, the present invention provides use of Form CSVI or Form CSVII for preparing a medicament for treating rheumatoid arthritis, Crohn's disease, ulcerative colitis, atopic dermatitis and psoriatic arthritis.

In the present invention, the "room temperature" is not a specific temperature but a temperature range of 10 to 30°C.

In the present invention, the "stirring" is performed using a conventional method such as magnetic stirring or mechanical stirring, and the stirring speed is 50 to 1800 r/min, preferably the magnetic stirring speed is 300 to 900 r/min, and the mechanical stirring speed is is 100 to 300 r/min.

Said "drying" is accomplished at room temperature or higher. The drying temperature is from room temperature to about 80°C, or 60°C, or 50°C, or 40°C. Drying time can be from 2 to 48 hours, or overnight. Drying is accomplished in a fume hood, forced air convection oven, or vacuum oven.

The "characteristic peak" refers to a representative diffraction peak used to distinguish crystals and can typically have a deviation of ±0.2° using CuKα radiation.

A "water-saturated solvent" is prepared by conventional methods in the art. For example, excess water is ultrasonically mixed with the corresponding solvent and the organic solvent phase is collected after settling and phase separation.

As used herein, "crystal" or "crystalline form" refers to a crystal or crystalline form identified by an X-ray diffraction pattern presented herein. Those skilled in the art can appreciate that X-ray diffraction pattern errors depend on instrument conditions, sample preparation and sample purity. The relative intensities of diffraction peaks in X-ray diffraction patterns can also vary with experimental conditions; therefore, the order of diffraction peak intensity cannot be considered the sole or determinative factor. Indeed, the relative intensities of diffraction peaks in X-ray powder diffraction patterns are related to the preferred orientation of the crystals, and the diffraction peak intensities shown herein are exemplary, and identical diffraction peak intensities are not required. Accordingly, it will be understood by those skilled in the art that the crystalline forms of the present invention do not necessarily have exactly the same X-ray diffraction pattern as the examples shown herein. Any crystalline form whose X-ray diffraction pattern has the same or similar characteristic peaks should be within the scope of the present invention. One skilled in the art can compare the patterns presented in the present invention with patterns of unknown crystalline forms to identify whether these two groups of patterns reflect the same or different crystalline forms.

In some embodiments, Form CSVI and Form CSVII of the present invention are pure and substantially free of any other crystalline forms. In the present invention, when the term "substantially free" is used to describe a novel crystalline form, the content of other crystalline forms in the novel crystalline form is less than 20% (w/w) , specifically less than 10% (w/w), more specifically less than 5% (w/w), even more specifically less than 1% (w/w).

In the present invention, the term “about,” when referring to a measurable value such as weight, times, temperature, etc., may be ±10%, ±5%, ±1%, ±0.5%, or even ±0.5% of a specified amount. It is meant to include a variation of 0.1%.

FIG. 1 shows the XRPD pattern of form CSVI.

FIG. 2 shows the TGA curve of form CSVI.

FIG. 3 shows the DSC curve of form CSVI.

FIG. 4 shows XRPD pattern overlays of form CSVI before and after storage (top to bottom: initial, 6 months storage at 40° C./75% RH (sealed), 6 months storage at 40° C./75% RH (open), 60 °C/75% RH (sealed) for 1 month storage).

Figure 5 shows XRPD pattern overlays of form CSVI before and after DVS (top: initial, bottom: after DVS).

6 shows the XRPD pattern of Form CSVII in Example 9. FIG.

7 shows the TGA curve of Form CSVII in Example 9. FIG.

8 shows the TGA curve of Form CSVII in Example 11. FIG.

9 shows the DSC curve of Form CSVII in Example 11. FIG.

FIG. 10 shows XRPD pattern overlays of form CSVII before and after storage (from top to bottom: initial, 6 months storage at 25° C./60% RH (sealed), 6 months storage at 25° C./60% RH (open), 40 C./75% RH (sealed) for 6 months, 60° C./75% RH (sealed) for 1 month).

Figure 11 shows XRPD pattern overlays of Form CSVII before and after DVS (top: initial, bottom: after DVS).

Figure 12 shows XRPD pattern overlays of Form CSVI during the manufacturing process (top to bottom: excipient blend, Form CSVI formulation, Form CSVI).

Figure 13 shows XRPD pattern overlays of Form CSVII during the manufacturing process (top to bottom: excipient blend, Form CSVII formulation, Form CSVII).

FIG. 14 shows the stability test (from top to bottom: initial storage at 25° C./60% RH (sealed, 1 g desiccant) for 3 months, storage at 40° C./75% RH (sealed, 1 g desiccant) for 3 months. FIG. 10 shows XRPD pattern overlays of Form CSVI formulations with interim storage).

FIG. 15 shows the stability test (from top to bottom: initial storage at 25° C./60% RH (sealed, 1 g desiccant) for 3 months, storage at 40° C./75% RH (sealed, 1 g desiccant) for 3 months Fig. 2 shows the XRPD pattern overlay of Form CSVII formulation by interim storage).

Figure 16 shows the dissolution curves of Form CSVI and Form C formulations in 0.1N HCl.

Figure 17 shows the dissolution curves of Form CSVII and Form C formulations in 0.1N HCl.

Figure 18 shows the dissolution curves of Form CSVII and Form C formulations in PBS, pH 6.8.

(detailed explanation)
The invention is further illustrated by the following examples describing in detail the preparation and use of the crystalline forms of the invention. It will be apparent to those skilled in the art that many changes in materials and methods can be effected without departing from the scope of the invention.

Abbreviations used in the present invention are explained as follows:
XRPD: X-ray powder diffraction DSC: Differential scanning calorimetry TGA: Thermogravimetric analysis DVS: Dynamic vapor sorption
¹ H NMR: proton nuclear magnetic resonance HPLC: high performance liquid chromatography FaSSIF: fasting simulated intestinal fluid FeSSIF: Fed-state simulated intestinal fluid PBS: phosphate buffered saline RPM: revolutions/minute

Equipment and methods used for data collection:
X-ray powder diffraction patterns in the present invention were obtained with a Bruker D2 PHASER X-ray powder diffractometer. The parameters of the X-ray powder diffraction method of the invention are as follows:
X-ray: Cu, Kα
Kα1 (Å): 1.54060. Kα2 (Å): 1.54439
Kα2/Kα1 intensity ratio: 0.50
Voltage: 30 (kV)
Current: 10 (mA)
Scanning range (2θ): 3.0 degrees to 40.0 degrees

Thermogravimetric analysis (TGA) data in the present invention were obtained by TA Q500. The parameters of the TGA method of the invention are as follows:
Heating rate: 10°C/min
Purge gas: Nitrogen

Differential scanning calorimetry (DSC) data in the present invention were obtained by TA Q2000. The parameters of the DSC method of the invention are as follows:
Heating rate: 10° C./min, unless otherwise specified.
Purge gas: Nitrogen

Dynamic Vapor Sorption (DVS) is measured via an SMS (Surface Measurement Systems Ltd.) intrinsic DVS instrument. The control software is the DVS Intrinsic control software. Typical parameters for the DVS test are:
Temperature: 25°C
Gas and Flow: _N2 , 200 mL/min
RH range: 0% RH to 95% RH

Proton nuclear magnetic resonance spectral data ( ¹ H NMR) were collected from a Bruker Avance II DMX 400M HZ NMR spectrometer. 1-5 mg of sample was weighed and dissolved in 0.5 mL of deuterated dimethylsulfoxide or deuterated methanol to obtain a solution with a concentration of 2-10 mg/mL.

According to the present invention, upadacitinib and/or salts thereof used as raw materials are in solid (crystalline or amorphous), oil, liquid form or solution. Preferably, upadacitinib and/or salts thereof used as raw materials are solids.

Upadacitinib and/or its salts (corresponding to the starting materials in the examples) used in the examples below were prepared by known methods, for example the method disclosed in WO2017066775A1. Unless otherwise noted, the following examples were carried out at room temperature.

Example 1 Preparation of Form CSVI Weigh 16.9 mg of upadacitinib and 9.8 mg of succinic acid into a glass vial and add 0.3 mL of water-saturated isopropyl acetate/tert-butyl methyl ether (1:2, v/v). rice field. The samples were then transferred to a 35° C. oven, stirred for about 4 days, and another 0.2 mL of isopropyl acetate/tert-butyl methyl ether (1:2, v/v) saturated with water was added. The sample was stirred in an oven at 35° C. for an additional 3 days to give a solid after isolation. The solid was stored under 40° C./75% RH open conditions for about 2 days and then form CSVI was obtained. The XRPD pattern of Form CSVI is substantially as shown in FIG. 1 and the XRPD data are listed in Table 1.

Example 2 Preparation of Form CSVI 1. Weigh 1086 g of upadacitinib and 0.5140 g of succinic acid into a glass vial and add 19.5 mL of tert-butyl methyl ether/isopropyl alcohol/water (10:1:0.1, v /v/v) was added. The sample was stirred at 5° C. for 50 minutes, then 55.4 mg of form CSVI species (Seed) was added. After stirring for an additional 17.5 hours at 55°C, the sample was cooled to 45°C and stirred for 1 hour. The sample was then cooled to 40°C and stirred for 190 minutes, then cooled to 35°C and stirred for 280 minutes, cooled to 25°C and stirred for 1 day. Another 1.0 mL of tert-butyl methyl ether/isopropyl alcohol/water (10:1:0.1, v/v/v) and 3.0 mL of n-heptane are added and the sample is incubated at 25° C. for approximately 4 days. Stirred. An additional 5.0 mL of n-heptane was added and a solid was isolated after stirring for an additional 5 hours at 25° C. (temperature for all the above procedures was controlled by a hot plate stirrer). The isolated solid was dried under vacuum at 75° C. for about 17.5 hours and subjected to open conditions of 40° C./75% RH for about 5 days to obtain Form CSVI. The TGA curve of Form CSVI shows a weight loss of about 1.2% when heated to 100° C., substantially as shown in FIG. The molar ratio of succinate to upadacitinib in form CSVI is 0.79:1 by ¹ H NMR.

Example 3 Preparation of Form CSVI 1.0236 g of upadacitinib and 0.2796 g of succinic acid were dissolved in 6 mL of n-propanol and the solution was filtered into a 60° C. jacketed reactor. After mechanical stirring for about 5-10 minutes, 10 mL of n-heptane was slowly added. 0.0500 g of form CSVI was weighed and dispersed evenly in 2 mL of n-heptane. The suspension was then added to the reactor. The system was aged at 60° C. for approximately 1 hour and cooled to 35° C. (within 5 hours). After about 13 hours of aging at 35° C., 18 mL of n-heptane was added dropwise (takes 3 hours) and the system was aged for an additional hour. The system was cooled to 5°C (takes 3 hours) and aged for about 15 hours. The wet cake obtained by filtration was dried at room temperature for about 9 hours and then vacuum dried in an oven at 75° C. for about 38 hours. The dried solid was jet milled (feed pressure 0.3 MPa, milling pressure 0.1 MPa) and vacuum dried in an oven at 75° C. for about 23 hours, then form CSVI was obtained. The DSC curve of Form CSVI is substantially as shown in Figure 3, with one endothermic peak appearing around 124°C (onset temperature). The molar ratio of succinic acid to upadacitinib in form CSVI is 0.63:1 by HPLC.

Example 4 Preparation of Form CSVI 1.0237 g of upadacitinib and 0.3413 g of succinic acid were dissolved in 6 mL of n-propanol and the solution was filtered into a 60° C. jacketed reactor. After mechanical stirring for about 5-10 minutes, 10 mL of n-heptane was slowly added. 0.0500 g of Form CSVI was weighed and then evenly dispersed in 2 mL of n-heptane, then the suspension was added to the reactor. The system was aged at 60° C. for approximately 1 hour and cooled to 35° C. (5 hours). After about 13 hours of aging at 35° C., 18 mL of n-heptane was added dropwise (takes 3 hours) and the system was aged for an additional hour. The reaction mass was cooled to 5° C. (takes 3 hours) and aged for about 15 hours. The wet cake obtained by filtration was dried at room temperature for about 9 hours and then vacuum dried in an oven at 75° C. for about 38 hours. The dried solid was jet milled (feed pressure 0.3 MPa, milling pressure 0.1 MPa) and vacuum dried in an oven at 75° C. for about 23 hours, then form CSVI was obtained. The molar ratio of succinic acid to upadacitinib in Form CSVI is 0.85:1 by HPLC.

Example 5 Kinetic Solubility of Form CSVI The solubility of Form C is disclosed in WO2017066775A1. Approximately 15-30 mg of Form CSVI of the present invention was suspended in 1.8 mL FeSSIF, 1.8 mL FaSSIF and 1.8 mL pH=7.4 PBS. After equilibrating for 24 hours and 48 hours, the concentration of upadacitinib in the saturated solution was tested by HPLC and the results are shown in Table 2.

The results show that form CSVI has higher solubility in FeSSIF, FaSSIF and pH=7.4 PBS.

Example 6 Stability of Form CSVI About 5 mg of Form CSVI of the present invention was stored under 40°C/75% RH and 60°C/75% RH conditions. Purity and crystal form were tested before and after storage by HPLC and XRPD. The results are listed in Table 3 and the XRPD overlay is substantially as shown in FIG.

The results show that form CSVI is stable under 40°C/75% RH (sealed) and 40°C/75% RH (open) conditions for at least 6 months. Form CSVI is found to have good stability under accelerated conditions. Form CSVI is stable under 60° C./75% RH (sealed) conditions for at least one month. Form CSVI is found to have good stability even under more stressful conditions.
About 10 mg of Form CSVI in the present invention was subjected to humidity cycles from 0% RH to 95% RH to 0% RH using a dynamic vapor sorption (DVS) analyzer. The crystalline morphology before and after humidity cycling was examined by XRPD and the results are shown in FIG. The results show that no morphological changes are observed after DVS testing, indicating that form CSVI has good stability in both high and low relative humidity.

Example 7 Preparation of Form CSVII 16.3 mg of upadacitinib and 11.5 mg of adipic acid were weighed into a glass vial and 0.3 mL of isopropyl acetate/tert-butyl methyl ether (1:3, v/v) was added. The sample was transferred to a 35°C oven and stirred for approximately 4 days. Another 0.2 mL of isopropyl acetate/tert-butyl methyl ether (1:3, v/v) was added. The samples were stirred in an oven at 35° C. for an additional 3 days and then at room temperature for 6 days. A solid was obtained after isolation. Form CSVII was obtained after vacuum drying at 30° C. overnight.

Example 8 Preparation of Form CSVII 195.8 mg of upadacitinib and 158.8 mg of adipic acid were weighed into a glass vial and 5 mL of isopropyl acetate/tert-butyl methyl ether (1:2, v/v) was added. The sample was stirred overnight at room temperature and 10.1 mg of Form CSVII species was added. The sample was stirred at room temperature for about an additional 5 days. A solid was obtained after isolation and dried under vacuum at 35° C. for 2.5 hours. 150.9 mg of the resulting solid was weighed into a glass vial, and 3.0 mL of tert-butyl methyl ether saturated with water was added. The sample was stirred at room temperature for about 2 days and isolated to give a solid. 25.4 mg of the resulting solid was placed under 40° C./75% RH conditions for about 1 day to obtain Form CSVII. The XRPD pattern of Form CSVII is substantially as shown in FIG. 6 and the XRPD data are listed in Table 4. The TGA curve of form CSVII shows a weight loss of about 1.2% when heated to 100° C., substantially as shown in FIG.

Example 9 Preparation of Form CSVII 1.0001 g of upadacitinib and 0.4228 g of adipic acid were dissolved in 6 mL of n-propanol/n-butanol (3:1, v/v) and the solution was then mechanically stirred. was filtered into the reactor for After raising the temperature of the reactor to 60° C., 10 mL of n-heptane was slowly added. 0.1018 g of Form CSVII was evenly dispersed in 2 mL of n-heptane and the suspension was slowly added to the reactor. After aging at 60° C. for 2 hours, the reaction mass was cooled to 35° C. (8 hours) and aged for an additional 5.5 hours. The suspension was filtered and the wet cake was washed with n-heptane. The wet cake was transferred to vacuum drying at 75° C. for about 16 hours to obtain Form CSVII. The molar ratio of adipic acid to upadacitinib in Form CSVII is determined by ¹ H NMR to be 0.65:1.

Example 10 Preparation of Form CSVII 0.9997 g of upadacitinib and 0.4611 g of adipic acid were dissolved in 6 mL of n-propanol/n-butanol (3:1, v/v) and the solution was then stirred mechanically. was filtered into a 50 mL reactor for After raising the temperature of the reactor to 60° C., 10 mL of n-heptane was slowly added. 0.1018 g of Form CSVII was suspended in 2 mL of n-heptane at room temperature and the suspension was slowly added to the reactor. After aging at 60° C. for 2 hours, the reaction mass was cooled to 35° C. (8 hours) and aged for an additional 5.5 hours. The suspension was filtered and the wet cake was washed with n-heptane. The wet cake was transferred to vacuum drying at 75° C. for about 16 hours to obtain Form CSVII. The molar ratio of adipic acid to upadacitinib in Form CSVII is determined by ¹ H NMR to be 0.77:1.

Example 11 Preparation of Form CSVII 501.2 mg of upadacitinib and 230.2 mg of adipic acid were weighed into a 50 mL reactor and 20 mL of isobutanol/n-heptane (1:3, v/v) was added. A clear solution was obtained when the system was mechanically stirred and the temperature was raised to 75°C. The system was cooled to 55°C and aged for 0.5 hours, then cooled to 45°C and aged for 0.5 hours. About 5 mg of Form CSVII was evenly dispersed in about 0.2 mL of iso-butanol/n-heptane (1:3, v/v) and the suspension was slowly added to the reactor. After aging for about 2 hours, the system was cooled to 25°C (which took 4 hours) and aged for about 85 hours. The suspension was filtered and the wet cake was washed with the filtrate. The wet cake was vacuum dried at 50° C. for about 24 hours followed by drying at room temperature for about 8.5 hours. The solid was then vacuum dried in an oven at 75° C. for about 15 hours to obtain Form CSVII. The TGA curve of form CSVII shows a weight loss of about 0.1% when heated to 100° C., substantially as shown in FIG. The DSC curve for Form CSVII is substantially as shown in Figure 9, with one endothermic peak appearing at about 105°C (onset temperature). The molar ratio of adipic acid to upadacitinib in Form CSVII is determined by ¹ H NMR to be 0.99:1.

Example 12 Kinetic Solubility of Form CSVII The solubility of Form C is disclosed in WO2017066775A1. About 15-30 mg of Form CSVII in the present invention was suspended in 1.8 mL FeSSIF, 1.8 mL FaSSIF and 1.8 mL pH=7.4 PBS. After equilibration for 24 hours and 48 hours, the concentration of upadacitinib in the saturated solution was tested by HPLC and the results are shown in Table 5.

The results show that form CSVII has higher solubility in FeSSIF, FaSSIF and pH=7.4 PBS.

Example 13 Stability of Form CSVII About 5 mg of Form CSVII in the present invention was stored under 25°C/60% RH, 40°C/75% RH and 60°C/75% RH conditions. Purity and crystal form were tested before and after storage by HPLC and XRPD. The results are listed in Table 6 and the XRPD overlay is substantially as shown in FIG.

The results show that Form CSVII is stable for at least 6 months under 25°C/60% RH and 40°C/75% RH (closed) conditions. Form CSVII is found to have good stability under long-term and accelerated conditions. Form CSVII is stable under 60° C./75% RH (sealed) conditions for at least one month. Form CSVII is found to have good stability even under more stressful conditions.

About 10 mg of Form CSVII in the present invention was subjected to humidity cycles from 0% RH to 95% RH to 0% RH using a dynamic vapor sorption (DVS) analyzer. The crystalline morphology before and after humidity cycling was tested by XRPD and the results are shown in FIG. The results show that no morphological changes are observed before and after the DVS test, indicating that Form CSVII has good stability in both high and low relative humidity.

Example 14 Formulation Preparation Formulation and preparation processes for Form CSVI, Form CSVII and Form C are shown in Tables 7 and 8. XRPD overlays before and after the formulation process are shown in Figure 12 (Form CSVI) and Figure 13 (Form CSVII), demonstrating that Form CSVI and Form CSVII are physically stable after the formulation procedure.

Example 15 Stability of Formulations Tablets of Form CSVI and Form CSVII obtained in Example 14 were packed in HDPE bottles with 1 g desiccant and stored under 25° C./60% RH and 40° C./75% RH conditions. bottom. The samples were tested for crystalline morphology and impurities and the results are listed in Table 9. The results show that the products of Form CSVI and Form CSVII remain stable under 25° C./60% RH and 40° C./75% RH conditions for at least 3 months with essentially no change in purity.

Example 16 Dissolution of Form CSVI Dissolution testing was performed on Form CSVI and Form C formulations obtained from Example 14, methods and parameters are listed in Table 10. Dissolution data for Form CSVI formulations are shown in Table 11 and Figure 16, indicating that the cumulative drug release of Form CSVI at 30 minutes exceeded 85%, which meets the criteria for rapid dissolution. On the other hand, the dissolution rate of form CSVI is higher than that of form C in 0.1N HCl, suggesting that the in vivo bioavailability of form CSVI is superior to that of form C.

Example 17 Dissolution of Form CSVII Form CSVII and Form C formulations obtained from Example 14 were subjected to dissolution testing and the test methods are shown in Table 12. Dissolution data for Form CSVII formulations are shown in Tables 13-14 and Figures 17-18, demonstrating that the cumulative drug release of Form CSVII in 0.1 N HCl in 30 minutes exceeded 85%, meeting the criteria for rapid dissolution. Indicated. On the other hand, the dissolution rate of Form CSVII is higher than Form C in both 0.1 N HCl and pH 6.8 PBS, suggesting that Form CSVII has better in vivo bioavailability than Form C.

The above examples are merely to illustrate the technical concepts and features of the present invention, and are intended to enable those skilled in the art to understand and thereby implement the present invention. and should not be concluded to limit the protection scope of the present invention. Any equivalent variation or modification in accordance with the spirit of the present invention should be covered by the protection scope of the present invention.

Example 2 Preparation of Form CSVI 1. Weigh 1086 g of upadacitinib and 0.5140 g of succinic acid into a glass vial and add 19.5 mL of tert-butyl methyl ether/isopropyl alcohol/water (10:1:0.1, v /v/v) was added. The sample was stirred at 55 ° C. for 50 minutes, then 55.4 mg of form CSVI seed (Seed) was added. After stirring for an additional 17.5 hours at 55°C, the sample was cooled to 45°C and stirred for 1 hour. The sample was then cooled to 40°C and stirred for 190 minutes, then cooled to 35°C and stirred for 280 minutes, cooled to 25°C and stirred for 1 day. Another 1.0 mL of tert-butyl methyl ether/isopropyl alcohol/water (10:1:0.1, v/v/v) and 3.0 mL of n-heptane are added and the sample is incubated at 25° C. for approximately 4 days. Stirred. An additional 5.0 mL of n-heptane was added and a solid was isolated after stirring for an additional 5 hours at 25° C. (temperature for all the above procedures was controlled by a hot plate stirrer). The isolated solid was dried under vacuum at 75° C. for about 17.5 hours and subjected to open conditions of 40° C./75% RH for about 5 days to obtain Form CSVI. The TGA curve of Form CSVI shows a weight loss of about 1.2% when heated to 100° C., substantially as shown in FIG. The molar ratio of succinate to upadacitinib in form CSVI is 0.79:1 by ¹ H NMR.

Claims (17)

Crystalline form CSVI is a crystalline form CSVI of upadacitinib, which is a co-crystal of upadacitinib and succinic acid.
X-ray powder diffraction patterns were obtained using CuKα radiation with 2-theta values of 4.7° ± 0.2°, 6.2° ± 0.2° and 22.7° ± 0.2° for one or 2. Crystal form CSVI according to claim 1, which exhibits two or three characteristic peaks. X-ray powder diffraction patterns were obtained using CuKα radiation with 2-theta values of 15.8° ± 0.2°, 17.3° ± 0.2° and 23.5° ± 0.2° for one or 2. Crystal form CSVI according to claim 1, which exhibits two or three characteristic peaks. X-ray powder diffraction patterns were obtained using CuKα radiation with 2-theta values of 11.1° ± 0.2°, 14.1° ± 0.2° and 13.1° ± 0.2° for one or 2. Crystal form CSVI according to claim 1, which exhibits two or three characteristic peaks. 2. Crystalline form CSVI according to claim 1, wherein the X-ray powder diffraction pattern is substantially as shown in FIG. A process for the preparation of crystalline form CSVI according to claim 1, the process comprising:
1) adding upadacitinib and succinic acid to a mixture of esters and ethers and stirring to obtain crystalline form CSVI; and stirring to obtain crystalline form CSVI. wherein said ester is isopropyl acetate, said ether is methyl tert-butyl ether, said alcohol is n-propanol, isopropanol, isobutanol or n-butanol, and said alkane is n-heptane. Item 6. The method according to item 6. Crystalline form CSVII is a crystalline form CSVII of upadacitinib, which is a co-crystal of upadacitinib and adipic acid.
X-ray powder diffraction patterns were obtained using CuKα radiation with 2-theta values of 4.8° ± 0.2°, 6.0° ± 0.2° and 22.4° ± 0.2° with one or 9. Crystal form CSVII according to claim 8, which exhibits two or three characteristic peaks. X-ray powder diffraction patterns were obtained using CuKα radiation with 2θ values of 21.1° ± 0.2°, 15.4° ± 0.2° and 16.2° ± 0.2° at one or 9. Crystal form CSVII according to claim 8, which exhibits two or three characteristic peaks. X-ray powder diffraction patterns were obtained using CuKα radiation at 2θ values of 25.4° ± 0.2°, 12.8° ± 0.2° and 20.2° ± 0.2° with one or 9. Crystal form CSVII according to claim 8, which exhibits two or three characteristic peaks. 9. Crystalline Form CSVII according to claim 8, wherein the X-ray powder diffraction pattern is substantially as shown in Figure 6. A process for the preparation of crystalline form CSVII according to claim 8, the process comprising:
1) adding upadacitinib and adipic acid to a mixture of esters and ethers and stirring to obtain crystalline form CSVII, or 2) adding upadacitinib and adipic acid to a mixture of alcohols and alkanes, stirring, isolating and then drying. to obtain crystalline form CSVII. wherein said ester is isopropyl acetate, said ether is methyl tert-butyl ether, said alcohol is n-propanol, isopropanol, n-butanol or isobutanol, and said alkane is n-heptane. Item 14. The method according to item 13. A pharmaceutical composition comprising a therapeutically effective amount of crystalline form CSVI according to claim 1 or crystalline form CSVII according to claim 8 and a pharmaceutically acceptable excipient. Use of crystalline form CSVI according to claim 1 or crystalline form CSVII according to claim 8 for the preparation of a JAK1 inhibitor. Use of crystalline form CSVI according to claim 1 or crystalline form CSVII according to claim 8 for preparing a medicament for treating rheumatoid arthritis, Crohn's disease, ulcerative colitis, atopic dermatitis and psoriatic arthritis .